12-alkoxy-11-oxygenated pregnanes



United States Patent C) 3,030,391 IZ-ALKGXY-il-QXYGENATED PREGNANES Patrick A. Diassi, Westiield, N.J., assignor to Olin Mathieson Chemical Corporation, New York, N.Y., a

corporation of Virginia No Drawing. Filed May 29, 1961, Ser. No. 113,080 15 Claims. (Cl. 260397.45)

This invention relates to synthesis of steroids and more particularly to the prepartion of 12-alkoxypregnanes.

One object of this invention is the provision of advantageous processes for preparing steroids of the pro- The preferred compounds of this invention are those which are comprehended by the general formula:

wherein Y and Y' are the same or different and represent either a =C=O or a radical, wherein R is hydrogen or the acyl radical of a hydrocarbon carboxylic acid of less than twelve carbon atoms; Z represents either a =C=O or a radical; and R is lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, n-pentyl, and n-hexyl).

Representative compounds of this invention include, inter alia, 12a-(l0wer alkoXy)-1lfi-hydroxyprogesterones, such as 12a-methoxy-1lfi-hydroxyprogesterone and 121xethoxy-l 1 fi-hydroxyprogesterone; 12cc-(1OW61 alkoxy) -1 1- ketoprogesterones, such as IZa-methOXy-ll-ketoprogesterone and 12a-ethoxy-1l-ketoprogesterone; 12a-(lower alkoxy)-A -pregnene-3fl,l1,6,20/9-triols, such as 12a-methoxy-A -pregnene-3fL1 1fl,20fi-triol and lZa-ethoxy-M-pregnene-3B,11}3,20,B-triol; 3,20-diesters of 12a-(lower alkoxy)-A -pregnene-3]3,11,3,20,3-triols, such as the diesters with hydrocarbon carboxylic acids of less than twelve carbon atoms, as-exemplified by the lower alkanoic acids (e.g., acetic, propionic and butyric acid), the lower alkenoic acids, the monocyclic aryl carboxylic acids (e.g., benzoic acid), the monocyclic ar(loweralkanoic) acids (e.g., phenacetic and fl-phenylpropionic acid), the cycloice alkanecarboxylic acids (e.g., cyclohexanecarboxylic acid), and the cycloalkenecarboxylic acids; 12a-(lower alkoxy)- M-pregnene-l1,8,20B-diol-3-ones, such as l2a-methoxy- M-pregnene-l15,20,8-diol93-one and 12u-ethoxy-A -pregnene-11fi,20B-diol-3-one; and 20-monoesters of 12a-(lower alkoxy)-A -pregnene-l15,20fl-diol-3-ones, such as the monoesters with the hydrocarbon carboxylic acids listed hereinbefore.

The steroids of this invention can be prepared by a number of ditferent processes. According to one process, 9u-bromo-1l-ketoprogesterone is treated with an alkali lower alkoxide in the lower alkanol (e.g., sodium methoxide in methanol) whereby the coresponding IZa-(IOWCI alkoxy)-1l-ketoprogesterone is obtained. Alternatively, 115,12B-epoxyprogesterone can be treated with a lower alkanol in the presence of a strong acid, such as perf chloric acid, to yield the corresponding 12a-(lower alkoxy)-1lfi-hydroxyprogesterone, which, if desired, can be oxidized by treatment with a hexavalent chromium compound, such as chromic anhydride, toyield the corresponding 12a (lower alkoxy)-1l-ketoprogesterone.

12oc-(lOW61' a1koxy)-1l-ketoprogesterone can then be I reduced, as by treatment with lithium aluminum hydride,

to yield the corresponding l2 u-(lower alkoxy)-A -pregnene-3B,11;8,20B-triol derivative, which, if desired, can be esterified to yield the 3,20-diester in the usual manner by treatment with an acyl chloride or acid anhydride in the presence of an organic base such as pyridine. The preferred esterifying agents are the acyl chlorides and acid anhydrides of hydrocarbon carboxylic acids of less than twelve carbon atoms, as exemplified by the hydrocarbon carboxylic acids listed hereinbefore.

The 12a-(lower alkoxy)-A -pregnene-3fi,l1,6,20/3-triols can, if desired, be selectively oxidized by treatment with manganese dioxide to yield the corresponding 12a-(lower alkoxy) -A -pregnene-1 1fl,20/8-diol3-ones, which may then, if desired, be esterified by treatment with one of the acylating agents listed hereinbefore to yield the 20-monoester derivative.

The compounds of this invention are pharmacologically-active steroids, useful as progestational agents. Hence the new compounds of this invention can be used in lieu of known progestational steroids in the treatment of functional uterine bleeding, for example, with concentration and/or dosage based on the activity of the particular compound.

The following examples are illustrative of the invention (all temperatures being in centigrade):

EXAMPLE 1 1 Za-M ethoxy-I 1 5-H ydroxy progesterone km; 242 mp (c=l6,400) A235,? 2.74, 2.92, 5.88, 6.04, 6.20;]. Analysis.Calcd. for C H O C, 73.30; H, 8.95; OCH 8.60. Found: C, 73.30, H, 8.88; OCH 8.92.

' EXAMPLE 2 1 2 a-Ethoxy-l 1 5-H ya'roxy progesterone Following the procedure of Example l'but substituting 5 ml. of ethanol for the methanol, 12a-ethoxy-l1p-hydroxyprogesterone is obtained.

In a similar manner, propanol, isopropanol, n-butanol and n-pentanol yield 12a-propoxy-1lfi-hydroxyprogesterone, 12a-isopropoxy-1lfi-hydroxyprogesterone, 12a-n-butoxy-llp-hydroxyprogesterone and IZOC-H-PBHYOXY-l lfi-hydroxyprogesterone, respectively.

EXAMPLE 3 1 Za-MethOxy-I 1 -Ketpr0gester0ne To a stirred suspension of 10 g. of 9a-bromo-11-ketoprogesterone in 300 ml. of methanol which has been flushed with nitrogen, 25 m1. of 2 N sodium metho-xide in methanol are added and the mixture stirred under nitrogen at room temperature for 2 /2 hours during which time the steroid dissolves. The solution is then neutralized with 10% acetic acid, diluted with 500 ml. of Water and extracted three times with 200 ml. portions of chloroform. The chloroform is washed with water and evaporated to dryness, in vacuo. The residue (9.4 g.) is dissolved in 60 ml. of benzene diluted with 120 ml. of hexane and adsorbed onto 200 g. of Woelm neutral alumina. Elution with benzene-hexane (3:1) or benzene gives a resi due on evaporation of the solvent which on crystallization from acetone-hexane gives about 3.2 g. of 12amethoxy-ll-ketoprogesterone having M.P. about I21- 122; [a] -|28l (chlf.);

mg, 235 mp. (e=19,200);

my? 2.99, 5.82, 6.02, 6.18 and 6.26,.

Analysis.Calcd. for C H O C, 73.71; H, 8.44; OCH 8.65. Found: C, 73.40; H, 8.30; OCH 8.76.

l2a-methoxy-1l-ketoprogesterone can also be obtained from 12a-methoxy-1lfi-hydroxyprogesterone as illustrated by the following example:

EXAMPLE 4 To a solution of 100 mg. of 12a-methoxy-11,B-hyd=roxyprogesterone in 4 ml. of acetone, 0.13 ml. of an aqueous solution containing 20.0 g. of chromic anhydride and 32.0 of sulfuric acid per 100 ml. is added dropwise. After stirring at room temperature for 15 minutes the excess chromic acid is decomposed by adding a few drops of methanol. The mixture is filtered and washed with acetone. The filtrate is then diluted with 10 ml. of water and extracted 3 x ml. of chloroform. The chloroform is washed with water and evaporated to dryness, in vacuo. Crystallization from acetone-hexane gives about 70 mg. of 12a-methoxy-1 l-ketoprogesterone.

EXAMPLE 5 1 Za-Ethoxy-I 1 -Ket0pr0gesterone To a solution of 200 mg. of 12a-methoxy-1l-ketoprogesterone in ml. of dry tetrahydrofuran 104 mg. of lithium aluminum hydride were added and the mixture stirred at room temperature for 3 hours. The excess lithium aluminum hydride was decomposed by adding a few drops of ethyl acetate the 20 ml. each of water and chloroform were added and the mixture acidified with dilute hydrochloric acid. I The chloroform was separated, washed with water until neutral and evaporated to dryness,

in vacuo, to yield a residue of l2a-methoxy-A -pregnene' 3B,11,8,20;3-trio1.

Sim-ilarily, 12a-ethoxy-1l-ketoprogesterone, 12a-propoxy-l l-ketoprogesterone, l2a-isopropoxy-1 l-ketoprogesterone, 12a n butoxy-l l-ketoprogesterone and 12a-npentoxy-11- ketoprogesterone yield, by the process of Example 6, 12a-ethoxy-A -pregnene-3B,11,8,20,3-triol, 12ccpropoxy-M-pregnene-SBJ16,20fi-triol, 12a-isopropoxy-A pregnene 3 6,11 5,2013 triol, 12a n butoxy-A -pregnene- 35,115,205-triol, and 1Za-n-pentoxy-A -pregnene-3 8,11,8, ZOB-triol, respectively.

EXAMPLE 7 12a-Methoxy-M-Pregncue-33,11,3,20fi-Tri0l 3 ,20- Diacetate 150 mg. of 12a-methoxy-A pregnene-3B,l1,8,20fi-triol is dissolved in 3 ml. of dry pyridine and 1 ml. of acetic anhydride is added. After 16 hours at room temperature ice water is added and the mixture is extracted with chloroform. The chloroform is washed successively with 2 N HCl, 5% NaHCO and water and then evaporated to dryness, in vacuo. Crystallization of the residue from acetonehexane gives about mg. of 12a-methoxy-A pregnene-3,8,11 3,20;8trio1 3,20-diacetate having melting point about 200-202";

Analysis.--Calcd. for C H O (448.58): C, 69.61; H, 8.99; OCH 6.92. Found: C, 69.16; H, 8.70; OCH 7.32.

Similarly, by substituting propionic anhydride and benzoyl chloride for the acetic .anhydride in Example 7, the 3,20-dipropionate and 3,20-dibenzoate of 12a-methoxy-A pregnene-313,115,20p-triol are formed, respectively. Furthermore, if other 12a-(lower alkoxy)-A -pregnene-3B, 11,9,20 3-triols of this invention are substituted for the 12amethoxy-A -pregnene-fifld1,8,20,6-triol in Example 7, the corresponding 3,20-diacetates are obtained.

EXAMPLE 8 1 Za-MethOxy-M-Pregnene-J 1/3,20;8-Di0l-3- On triol yield 12a-methoxy-A -pregnene-116,20fi-di01-3-one,

12a propoxy A pregnene-1 15,206-dio1-3-one, 12a-isopropoxy-M-pregnene-l113,20fl-diol-3-one, 12a-n-butoxy-A pregnene-11,8,20,8-diol-3-one and 12ot-n-pentoxy-A -preg nene-l16,206-diol-3-one, respectively.

EXAMPLE 9 1Za-Methoxy-A -Pregnene-11,8,20,8-Di0l-3-0ne ZO-Acetate "pregnene-115,20fl-diol-3-one Z O-acetate.

In a similar manner, the other 12ob-(lower alkoxy)-A pregnene-1118,20fi-diol-3-ones of this invention can be con verted to their ZO-acetate derivatives.

This invention may be variously otherwise embodied within the scope of the appended claims.

and

it e if r C=O wherein R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid of less than twelve carbon atoms; Z represents a radical selected from the group consisting of =C=O and and R is lower alkyl.

12a-(1ower alkoxy)-1lp-hydroxyprogesterone. 12a-methoxy-1 lfi-hydroxyprogesterone.

12a-(lower alkoxy)-1l-ketoprogesterone. IZa-methoxy-l l-ketoprogesterone.

12a-(1OW6I a1koxy)-A -pregnene-3/3,1113,20B-triol. 12a-methoXy-A -pregnene-3 5,1 1fi,20;8-triol.

12a-(lower a1koxy)-A -pregnene 3 3,115,205 triol, 3,20-di(lower alkanoate).

9. 12a-methoXy-A -pregnene-3p,115,20,8-triol, 3,20-diacetate.

10. IZoc-(IOWBI alkoxy)-A -pregnene-11,9,20,9-diol-3-one.

1 1. IZa-methoxy-M-pregnene-l 113,20/8-dio1-3-one.

12. 12a-(lower alkoxy)-A -preguene-115,2013-dio1-3-0ne 20-(l0wer alkanoate).

13. 12a-methoxy A pregnene-l1B,20 B-diol-3-one 20- acetate.

14. A process for preparing a 12a-(lower alkoxy)-l1flhydroxyprogesterone which comprises interacting 11 8,1213- epoxyprogesterone with a lower alkanol in the presence of a strong acid.

15. A process for preparing a 12a-(lower alkoxy)-11- ketoprogesterone which comprises interacting 9u-bromoll-ketoprogesterone with a lower alkanol and an alkali lower alkoxide.

sow ww References Cited in the file of this patent Sondheimer et al.: J.A.C.S., 5930-32 (1953). 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF STEROIDS OF THE GENERAL FORMULAE 